Vascular endothelial growth factor (VEGF) has long been considered a target for clinical intervention; however, its clinical relevance has yet to be proven. Elucidation of effectors downstream of VEGF may provide more sensitive drug targets for the use in angiogenic therapies for the treatment of cancer and cardiovascular diseases. Although precise mechanisms regulating angiogenesis remain to be delineated, it is generally accepted that VEGF is the main inducer of the angiogenic switch; its induction is controlled in part by hypoxia, it is expressed by a majority of tumor cells and it promotes endothelial cell (EC) proliferation, migration and tube formation. We have uncovered a novel VEGF signaling pathway that leads to the regulation of Akt3 through the sphingosine-1 -phosphate (S1P) receptor, Edg3, a G-protein coupled transmembrane receptor involved in the regulation of angiogenesis. Gene blocking has defined a discrete role for Akt3 downstream of VEGF signaling, the control of mitochondria! biogenesis. This pathway is independent of other Akt family members. Signaling pathways that coordinate mitochondrial biogenesis with cellular energy demands as they relate to processes such as angiogenesis, that involve new tissue production are poorly understood. The findings presented here support the hypothesis that Akt3 is a key regulator of VEGF-induced cellular energetics in primary endothelial cells. Experimentation is designed to 1. test and extend the model that VEGF acts through the Edg3 receptor to promote Akt3 expression, 2. determine the mechanism Akt3 regulates mitochondrial biogenesis and 3. use the Akt3 null animals to confirm the relevance of Akt3 in the regulation of mitochondrial biogenesis. Delineation of this novel pathway and its regulation of mitochondrial biogenesis is a prerequisite to designing new angiogenic therapies for the treatment of a broad range of human diseases linked to mitochondrial function. In addition these findings may provide important insights into fundamental processes beyond the scope of angiogenesis. [unreadable] [unreadable] [unreadable]